Regional citrate anticoagulation

ABSTRACT

A system or method automates and optimizes citrate anticoagulant supplementation in a blood filtration circuit during CRRT. A processor-based control system interfaces with a blood filtration circuit to detect patient blood flow into the circuit, detect fluid loss through a hemofilter, and sense vital electrolyte concentrations in the blood flow, and in response, control the addition of citrate, substitution fluid, and electrolyte supplements to ensure stability of plasma concentrations in post-dilution flow returned to the patient. The controller executes the method embodied as process control algorithms for calculating an optimal citrate flow rate as a function of selected, detected, and calculated system parameters. Citrate may be added to the circuit separately, or as part of a substitution solution or a dialysate.

PRIORITY CLAIM AND CROSS-REFERENCE TO RELATED APPLICATIONS

The present Application for Patent is a continuation application of andclaims priority to U.S. patent application Ser. No. 11/525,800 entitled“Automation and optimization of CRRT treatment using regional citrateanticoagulation” filed on Sep. 21, 2006, expressly incorporated hereinby reference, which is a non-provisional of and claims priority toProvisional Application 60/719,718 entitled “Citrate expert system”filed on Sep. 22, 2005, expressly incorporated herein by reference. Thepresent Application is related to and hereby incorporates by referencethe following commonly owned patent publications: “REGIONAL CITRATEANTICOAGULATION,” application Ser. No. 13/174,217; and “FLOW BALANCINGSYSTEM AND METHOD, ESPECIALLY FOR CITRATE,” application Ser. No.13/185,147.

BACKGROUND

1. Field

The present invention relates generally to blood filtration and tocontinuous renal replacement therapy (CRRT). More specifically, theinvention relates to automatic control and optimization of citrate flowrate, and fluid exchange flow rates, during CRRT therapy.

2. Background

There are many continuous renal replacement therapies (CRRT) commonlyused for treating patients suffering loss or impairment of natural renalfunctions. In a typical CRRT, blood is removed from a patient and pumpedthrough an extracorporeal circuit that includes an artificial kidney.The artificial kidney contains a hemofilter or semi-permeable membrane.The blood is circulated along one surface of the membrane, and adialysate fluid is circulated along the opposing surface. Throughosmosis or differential pressure, the hemofilter allows migration ofsoluble waste and water from the blood across the membrane and into thedialysate solution. The filtered blood is then returned to the patient.

Generally, CRRT therapies remove water and waste solute at a slow andsteady rate over long periods of time to ensure hemodynamic stability.In order maintain a constant total blood volume of a patient undergoingCRRT, a substitution fluid is introduced into the bloodstream in theextracorporeal circuit. Depending on the type of CRRT used, thesubstitution fluid may be introduced either upstream or downstream ofthe hemofilter. The composition of the substitution fluid, thecomposition of the dialysate, the flow rates of blood and dialysate, thepressure gradient across the membrane, and the composition of themembrane all contribute to the effectiveness of CRRT treatment.

Some of the more common CRRT methods in use today includeultrafiltration, hemodialysis, hemofiltration, and hemodiafiltration.Ultrafiltration describes any method that relies on movement of waterfrom blood across a semi-permeable membrane, due to a pressure gradientacross the membrane. Hemodialysis involves convective diffusion ofsolutes from blood across a semi-permeable membrane into a volume ofdialysate flow. The dialysate is made to flow on one side of themembrane in a direction opposite the flow of blood on the other side ofthe membrane to maintain a concentration gradient across the membrane.Hemofiltration operates without a dialysate, and instead uses a positivehydrostatic pressure to drive water and solutes across a more porousmembrane. Hemodiafiltration is a combination of hemodialysis andhemofiltration methods. In the literature, these therapies may be morespecifically defined according to the patient access and return sites,and to fluid transfer characteristics, e.g. continuous venous-venoushemofiltration (CVVH), continuous venous-venous hemodialysis (CVVHD),continuous venous-venous hemodiafiltration (CVVHDF), high volumehemofiltration (HVHF), etc.

One problem common to all CRRT therapies is blood coagulation in theextracorporeal circuit, and primarily across the membrane within theartificial kidney. To prevent blood coagulation, an anticoagulant istypically added to the bloodstream in the extracorporeal circuitupstream of the hemofilter. Historically heparin has been used as apreferred anticoagulant, and more recently, citrate ions in the form oftrisodium citrate have been proven effective in CRRT as ananticoagulant. A substitution fluid for use in hemofiltration that usescitrate as an anticoagulant, as well as additional background on citrateanticoagulation and CRRT therapies, are disclosed in U.S. Pat. No.6,743,191, which is fully incorporated herein by reference.

One significant concern arising from the use of citrate as ananticoagulant is its effect on blood electrolyte levels. Citrate ionsbond to positively charged electrolytes such as calcium and magnesium,thus, any passage of the citrate through the hemofilter and into thedialysate depletes these electrolytes from the bloodstream. If theproper electrolyte levels are not maintained during CRRT, in the worstcase, hypocalcemia or hypomagnesemia may be induced in the patient andcause life-threatening complications.

Previous methodologies have been proposed for fixing citrate flow rateas a function of blood flow rate during CRRT. However, the results varywidely, and provide only general guidelines that do not necessarilyoptimize treatment in a specific case. Oudemans-van Straaten, H. M.,“Guidelines for Anticoagulation in Continuous Venovenous Hemofiltration(CVVH),” recommends a citrate flow rate (CFR) of 35 mmol/h for a bloodflow rate (BFR) of 200 ml/min. The “Monza protocol”, promoted by theItalian Association of Pediatric Hematology and Oncology (AIEOP) et al.,recommends a CFR of 52.5 mmol/h for the same BFR. Strake, (no citationavailable) extrapolated to 200 ml/min BFR, recommends a CFR of 33.3mmol/h. Mehta, R. L. et al., “Regional Citrate Anticoagulation forContinuous Arteriovenous Haemodialysis in Critically Ill Patients,”Kidney Int. 1990, Vol. 38(5), pp. 976-981, extrapolated to 200 ml/minBFR, recommends a CFR of 38.1 mmol/h. Kutsogiannis, D. J. et al.,“Regional Citrate Anticoagulation in Continuous VenovenousHaemodiafiltration,” Am. J. Kidney Dis. 2000, Vol. 35(5), pp. 802-811,extrapolated to 200 ml/min BFR, recommends 40 mmol/h CFR. Palsson, R. etal., “Regional Citrate Anticoagulation in Continuous VenovenousHaemofiltration in Critically Ill Patients with a High Risk ofBleeding,” Kidney Int. 1999, Vol. 53, pp. 1991-1997, extrapolated to 200ml/min BFR, recommends a CFR of 20.6 mmol/h. Tolwani, A. J. et al.,“Simplified Citrate Anticoagulation for Continuous Renal ReplacementTherapy,” Kidney Int. 2001, Vol. 60, pp. 370-374, extrapolated to 200ml/min BFR, recommends a CFR of 28 mmol/h. Cointault, O. et al.,“Regional Citrate Anticoagulation in Continuous VenovenousHaemodiafiltration Using Commercial Solutions,” Nephrol. Dial.Transplant., January 2004, Vol. 19(1), pp. 171-178, extrapolated to 200ml/min BFR, recommends a CFR of 45.6 mmol/h. Taken as a whole, theavailable literature provides no consensus for optimizing regionalcitrate anticoagulation.

During administration of CRRT, regardless of CRRT type and protocol,multiple parameters in the blood filtration circuit must be maintainedunder strict control to ensure patient stability. Blood chemistry, bloodand fluid flow rates, dialysate concentration, substitution fluidconcentration, ultrafiltration rate, filter pressure drop, and fluidtemperatures and pressures are some of the many parameters that must becarefully monitored and adjusted to ensure proper administration of thetherapy. Depending on the particular blood chemistry and physicalcondition of the patient, the various flow rates and concentrations mayneed to be more finely adjusted. A source of citrate ions introduced inthe system adds another dimension of complexity. What is needed is anexpert system for controlling these parameters according to the needs ofthe individual patient.

SUMMARY

The present invention provides a system or method for automating andoptimizing citrate anticoagulant supplementation in a blood filtrationcircuit during CRRT. In an extracorporeal blood filtration circuit suchas a dialysis machine, one embodiment of the invention may comprise acontrol system and related components that interface with such anexisting machine, or it may comprise the entire extracorporeal fluidmechanical circuit and attendant control system. One embodiment of amethod according the invention may comprise a series of process stepsstored in a computer program for controlling the system, its components,and instrumentation, or for providing a health care technician withinformation for effecting manual controls.

A system according to one embodiment of the invention may comprise ablood flow detector for detecting a flow of blood from a patient accesssite into the blood filtration circuit, an electrolyte sensor fordetecting a concentration of various electrolytes present in the bloodflow, a source of citrate solution having a selected citrateconcentration, a citrate pump for causing flow of the citrate solutioninto the blood filtration circuit, and a controller such as a computerprocessor coupled to memory, for controlling the flow from the citratepump. In one aspect, the controller may effect citrate pump flow byexecuting a control algorithm that calculates an optimal citrate flowrate as a function of the detected blood flow, the sensed electrolyteconcentration, and the selected citrate concentration, each of which maybe transmitted as an input signal to the controller.

In various embodiments, the electrolyte sensor may sense one or morevital electrolytes such as calcium and magnesium ions that may be lostfrom patient blood plasma through the filtration process. An embodimentof the system may be further configured with a source of supplementalelectrolyte solution, an electrolyte pump, and related instrumentationfor detecting fluid loss rate through a hemofilter and for controllingelectrolyte solution flow. Another embodiment of the system may befurther configured with a source of substitution solution, asubstitution solution pump, related instrumentation, and controlalgorithms for adding pre-dilution and/or post-dilution flow ofsubstitution solution to the blood flow. In other embodiments, thesystem may add citrate to the blood flow as part of a substitutionsolution, or with a dialysate. Based on selected, detected, orcalculated system parameters, the controller may optimize citrate flow,electrolyte flow, post-dilution flow, and other parameters to maintain adesired quality and flow of blood plasma returning to the patient.

A method according to one embodiment of the invention optimizes citrateanticoagulant supplementation in a blood filtration circuit during CRRTthrough execution of process steps. These steps may include detecting aflow rate of blood from a patient access site, detecting electrolyteconcentration in the blood flow, adding to the blood filtration circuita flow of citrate solution having a known citrate concentration, andcontrolling the flow rate of the citrate solution as a function of thedetected blood flow rate, the detected electrolyte concentration, andthe known citrate concentration. Other embodiments may includeadditional process steps for detecting specific vital electrolytes,detecting fluid loss rates through the hemofilter, detectingsupplemental electrolyte solution flow rates, detecting substitutionfluid flow rates, and in response, controlling system flow rates as afunction of selected, detected, or calculated system parameters tomaintain a desired quality and flow of blood plasma returning to thepatient. In alternative embodiments, a method may control the additionof citrate anticoagulant as part of a pre-dilution substitutionsolution, or as part of a dialysate. Any of the method steps may beembodied as software in computer readable media executable by aprocessor to effect automatic control of a CRRT system.

BRIEF DESCRIPTION OF THE DRAWINGS

The features, objects, and advantages of the invention will become moreapparent from the detailed description set forth below when taken inconjunction with the drawings, wherein:

FIG. 1 shows a schematic diagram of a system according to the inventionfor optimizing CRRT treatment using regional citrate anticoagulation.

FIG. 2 is a diagram of a blood filtration circuit for CRRT treatment,equipped for automated control using a system according to theinvention.

FIG. 3 is another diagram of a blood filtration circuit for CRRTtreatment, configured to provide substitution solution and supplementalelectrolytes from a common source.

FIG. 4 is another diagram of a blood filtration circuit for CRRTtreatment, configured to provide substitution solution and anticoagulantfrom a common source.

FIG. 5 shows an exemplary schematic diagram of a system according to theinvention for controlling components shown in FIGS. 1-3.

FIG. 6 is a flow chart showing a method according to the invention forcontrolling citrate pump flow rate during CRRT treatment using regionalcitrate anticoagulation.

FIG. 7 is a flow chart showing a method according to the invention forcontrolling electrolyte pump flow rate during CRRT treatment usingregional citrate anticoagulation.

FIG. 8 is a flow chart showing a method according to the invention forcalculating ultrafiltration rate during CRRT treatment using regionalcitrate anticoagulation.

FIG. 9 is a flow chart showing a method according to the invention forcontrolling post dilution flow rate during CRRT treatment using regionalcitrate anticoagulation.

FIG. 10 is a flow chart illustrating the interdependency of input andoutput parameters, derived from components of a blood filtrationcircuit, for automating and optimizing CRRT treatment according to theinvention.

DETAILED DESCRIPTION

An exemplary embodiment of the present invention provides an expertmethod or system for optimizing a CRRT therapy that uses a regionalcitrate anticoagulant. Exemplary embodiments of methods presented hereincalculate optimal flow rates for the introduction or passage of variousfluids through an extracorporeal fluid mechanical circuit employed foreffecting CRRT. Flow rate calculations may be performed using formulasthat rely on inputs representing fixed or measured parameters operatingthroughout the circuit. Calculated results may be manually transmittedby a technician reading the results and adjusting flow ratesaccordingly, or may be automatically transmitted from a centralprocessor as control signals in a system according to an embodiment ofthe invention that includes the processor, the calculation software, andthe extracorporeal circuit.

FIG. 1 shows a schematic diagram of one embodiment of a system 100according to the invention. System 100 may be used in combination withother CRRT equipment (such as a dialysis machine) to provide regionalcitrate anticoagulation. As such, some or all of the components ofsystem 100 may form an integral part of the extracorporeal circuit. Acentral computer or controller 11 may allow a user to manually orautomatically control other components within system 100. In basic form,these may include a blood flow detector 13, an electrolyte sensor 15, asource of citrate solution 17, and a citrate pump 19. Controller 11communicates with each of these components via signal line 12. Signalline 12 may be made up of one or more electrical cables or groups ofelectrical cables or buses suitable for analog or digital signaltransmission. In another embodiment, bus 12 may represent one or morewireless links.

Controller 11 may include a CPU 21, which may be a general purposecomputer, personal computer, or other suitable microprocessor-basedcomponent or microcontroller known in the art. A computer-readablememory 23, accessible by CPU 21, may be integral to CPU 21 or may beseparately coupled thereto. Memory 23 may include software, executableby CPU 21, for effecting various controller functions includingreceiving system input signals and transmitting output control signals.Memory 23 may also include any conventional operating system softwareessential for basic computing operations. Controller 11 may furtherinclude peripheral devices such as a display unit 25 and a userinterface 27. Display unit 25 and user interface 27 may assist a userduring manual operation of the system. For example, controller 11 mayperform a calculation for determining a flow rate within theextracorporeal circuit, and may display the results of the calculationon display unit 25. A user reading these results may then adjust acircuit component manually. Or, the user may adjust the componentremotely by manual entry of keystrokes on user interface 27.

Blood flow detector 13 detects the flow or flow rate of blood taken froma patient access site during CRRT. Blood flow detector 13 may be anycommercial detector known in the art and commonly used for this purpose,such as a non-invasive infrared or ultrasonic Doppler type detector. Inone embodiment, blood flow detector 13 may include a pressure sensor fordetecting a differential pressure between two points in the blood flow,for derivation of a signal representative of the blood flow.

Electrolyte sensor 15 may be any sensor or detection system capable ofanalyzing blood for the presence of specific electrolytes such as ionsof bicarbonate, calcium, chloride, copper, glucose, iron, magnesium,manganese, phosphate, potassium, sodium, or zinc. For example,electrolyte sensor 15 may be an electrochemical sensor such as acontinuous blood gas analyzer, an ionic conductive ceramic sensor, anion conductive electrode, or a sensor employing an ion sensitive fieldeffect transistor. Alternatively, electrolyte sensor 15 may include amass spectrometer for analyzing discrete samples taken from the bloodflow at predetermined time intervals. In one embodiment, electrolytesensor 15 senses calcium ion concentration and magnesium ionconcentration.

Citrate solution 17 may be any suitable container for containing avolume of citrate ions in solution. A transfusion or infusion bagcontaining a solution of citric acid or trisodium citrate of a selectedconcentration may be used for this purpose. Citrate pump 19 may beconnected to draw a flow from citrate solution 17 for supplementing theblood flow in the extracorporeal circuit. Citrate pump 19 may be anysuitable commercially available pump commonly used in the medical fieldfor pumping blood, such as a diaphragm, centrifugal, or peristalticpump.

System 100 operates by controller 11 receiving input signals from bloodflow detector 13 and electrolyte sensor 15, representing blood flow andelectrolyte concentration, respectively. Controller 11 may thencalculate an optimal citrate flow rate as a function of the detectedblood flow, the sensed electrolyte concentration, and the selectedcitrate concentration. In one embodiment, CPU 21 performs thiscalculation by executing an algorithm stored in memory 23. Controller 11then transmits an output signal representing the optimal citrate flowrate to citrate pump 19, which, in response to receiving the outputsignal, adjusts its speed to achieve the optimal flow rate.

In one embodiment of a system according to the invention, the algorithmfor calculating optimal citrate flow rate, E, may be expressed as E=f(A,B, C, D), where A is a blood flow rate detected by blood flow detector13, B is a calcium ion concentration detected by electrolyte sensor 15,C is a citrate concentration selected for citrate solution 17, and D isa magnesium ion concentration detected by electrolyte sensor 15. In oneembodiment, E may be expressed as:E=A×(B+D)/C  (1)

In another embodiment, citrate solution 17 may contain a selected citricacid concentration and a selected trisodium citrate concentration. Inthis embodiment, controller 11 may calculate an optimal citrate flowrate a function of blood flow, electrolyte concentration, citric acidconcentration, and trisodium citrate concentration. For example, tooptimize citrate flow rate during CRRT, controller 11 may control theflow rate E=f(A, B, C, D, G) of citrate pump 19 according to:E=A×(B+D)/(C+G)  (2)where A is a blood flow rate detected by blood flow detector 13, B is acalcium ion concentration detected by electrolyte sensor 15, C is acitric acid concentration selected for citrate solution 17, D is amagnesium ion concentration detected by electrolyte sensor 15, and G isa trisodium citrate concentration selected for citrate solution 17.

FIG. 2 illustrates another embodiment of the invention as a system 200,equipped for automated control, wherein citrate is added as apre-dilution anticoagulant solution. System 200 also includes additionalcomponents in a blood filtration or artificial kidney circuit that maybe used, for example, in CVVH or HVHF CRRT therapies.

A patient blood access site 29 provides a source for drawing a flow ofunfiltered blood 20 from a patient into the extracorporeal circuit. Ablood pump 31 provides the mechanical force required for sustaining acontinuous flow of blood. Like citrate pump 19, blood pump 31 may be anyconventional pump known in the medical arts and suitable for thepurpose, such as a peristaltic pump. Blood flow detector 13, which maybe a pressure sensor or flow monitor, measures the flow of blood drawnby blood pump 31. Blood flow detector 13 may transmit a feedback signalrepresenting the blood flow to a controller 11. Citrate pump 19supplements blood flow 20 with a flow 22 of citrate ion anticoagulantfrom citrate solution 17. Citrate solution 17 may contain a selectedconcentration of citric acid, trisodium citrate, and/or another sourceof citrate ions.

An optional anticoagulant, such as heparin, may be added upstream ofhemofilter 39 using a heparin pump 33 to inject a flow 24 into bloodflow 20. A pre-filter pressure sensor 35 measures pressure in blood flow20 upstream of hemofilter 39. Pressure sensor 35 may transmit a signalrepresenting pressure or flow to a controller 11. Also upstream ofhemofilter 39, a pre-dilution pump 37 may further supplement theunfiltered blood flow 20 with a flow 26 from a source of substitutionfluid 43. Particularly for HFHV therapies, a substitution fluid 43 maybe necessary to maintain an adequate volume of blood plasma in thepatient. Substitution fluid 43 may be any sterile intravenous fluidhaving a concentration of electrolytes similar to the plasma.

Hemofilter 39 transfers water and waste solutes out of the blood. DuringCRRT, hemofilter 39 performs the function of an artificial kidney ordialysis filter. The hemofilter 39 may be constructed with two flowpaths separated from each other by a semi-permeable membrane. One flowpath passes blood flow 20, while the second flow path 32 passes adialysate, preferable in a direction opposite that of blood flow 20, topromote a diffusion gradient. As in conventional dialysis systems, thedialysate contains a concentration of solutes of lower concentrationthan what is found in the unfiltered blood flow 20. Through osmosisand/or differential pressure across the semi-permeable membrane,hemofilter 39 removes unwanted waste products from blood flow 20 forentrainment in dialysate flow path 32.

A filtration pump 49, which may be similar in construction to otherpumps in the circuit, draws dialysate from hemofilter 39 into thedialysate flow path 32, which leads to a dialysate collector 51. Afiltrate pressure sensor in flow path 32 may be installed for detectionof dialysate flow rate, and transmission of a feedback signalrepresenting dialysate flow rate to controller 11. Dialysateaccumulating in collector 51 may be disposed of as a waste product.

The dialysate in flow path 32 may be routed through a blood leakdetector 46, which may be set to alarm upon detection of excessivepresence of blood plasma in dialysate flow path 32. One example of ablood leak detector 46 is a non-invasive optical sensor manufactured byIntrotek Intl. of Edgewood, N.Y. The Introtek leak detector operates onthe principle of light absorption. Dialysate flow is routed to the leakdetector through clear plastic tubing, into which a beam of light isdirected. The specific amount of light absorbed by the dialysate iscompared to a calibrated pre-set threshold. If the threshold is exceededdue to the presence of too much blood leaking into flow path 32 througha perforation in the membrane of hemofilter 39, the optical leakdetector may output an analog or digital alarm signal to indicate anout-of-tolerance condition. In one embodiment, controller 11 may receivethis alarm, and in response, shut down blood pump 31, therebyinterrupting the CRRT until hemofilter 39 can be replaced.

A flow 40 of filtered blood exits hemofilter 39 on the downstream sideof the filter. An electrolyte sensor 15 may be installed in the exitflow 40 to sense various electrolyte levels and transmit signalsrepresenting those levels to a controller 11. A post-dilution flow 28may supplement filtered blood flow 40 downstream of hemofilter 39. Apost-dilution pump 53 draws flow 28 from a source of substitution fluid.In one embodiment, source 43 provides the source of substitution fluidfor both pre-dilution pump 37 and post-dilution pump 53.

In the embodiment shown, pre-dilution flow 26 and post-dilution flow 28originate from a common flow 30 of substitution fluid exiting source 43.A temperature sensor 55 and heater 57 may be installed in the flow pathsof substitution fluid, preferably within the path of common flow 30, tocontrol substitution fluid temperature. Temperature sensor 55 maytransmit an analog or digital signal representing substitution fluidtemperature to controller 11. In response to receiving a temperaturesignal, controller 11 may switch on or off heater 57, or otherwiseadjust the output of heater 57, for example, by transmitting a controlsignal that varies the amount of electrical current energizing anelectric heating element of heater 57. In this way, the temperature offiltered blood flow 40 may be maintained at an optimal level whendelivered back to the patient.

A post-filter pressure sensor 41 may be placed into the path of bloodflow 40 for making pressure and flow measurements downstream ofhemofilter 39. Pressure sensor 41 may transmit a signal representingpressure or flow to a controller 11. An air bubble trap 61 may be placedinto blood flow 40 for removal of unwanted micro bubbles.

An electrolyte source 63 may be provided for replenishing blood flow 40with electrolytes such as bicarbonate, calcium, chloride, copper,glucose, iron, magnesium, manganese, phosphate, potassium, sodium, andzinc that may have been depleted through filtration. In one embodiment,electrolyte source 63 provides a solution containing calcium ions andmagnesium ions, contained, for example, in a transfusion or infusionbag. An electrolyte pump 65, which may be similar in construction toother pumps in the circuit, draws the electrolyte solution fromelectrolyte source 63 into a flow 36 that supplements blood flow 40.

An air bubble detector 67 may be placed into blood flow 40 downstream ofbubble trap 61, and preferably downstream of all pumps in the circuit,to detect the undesirable presence of air bubbles or air gaps in bloodflow 40. Any air bubble detector known in the medical arts, such asthose operating on ultrasonic or infrared sensing technology, may beused for this purpose. An automatic clamp 69 may be placed between airbubble detector 67 and patient blood return site 71. In one embodiment,a solenoid valve may be employed as automatic clamp 69. In anotherembodiment, air bubble detector 67 and automatic clamp 69 interfaceelectronically with controller 11. In response to detecting passage ofan air gap or air bubble, air bubble detector may transmit an alarmsignal to controller 11. In response to receiving the alarm signal,controller 11 may output an actuation signal to automatic clamp 69,causing it to arrest the blood flow. In another embodiment, the sameactuation signal may shut off blood pump 31.

FIG. 3 is another diagram of a blood filtration circuit for CRRTtreatment that may be optimized for regional citrate anticoagulationaccording to an embodiment of the invention. This embodiment may besuitable for CVVH type therapy. System 300 shown in FIG. 3 may beconfigured to provide substitution solution and supplementalelectrolytes from a common source.

System 300 operates similarly to system 200. However, in system 300,substitution fluid may be introduced only as post-dilution fluid,downstream of hemofilter 39, by post-dilution pump 53. No pre-dilutionflow of substitution fluid is provided. System 300 may also becharacterized by the absence of a separate electrolyte pump.Post-dilution pump 53 may provide both substitution fluid andsupplemental electrolyte solution, thereby eliminating the need for theelectrolyte pump. The supplemental electrolytes may be included withinsubstitution fluid 44, or the electrolytes may be provided from aseparate source coupled to pump 53. In one embodiment, the supplementalelectrolytes are provided by a chloride-based solution that includescalcium and magnesium ions.

FIG. 4 illustrates another blood filtration circuit for optimizing CRRTusing regional citrate anticoagulation according to an embodiment of theinvention. In this embodiment, suitable for CVVH or CVVHD, system 400 isconfigured to provide substitution solution and citrate anticoagulantfrom a common source. The common source may be connected to provide apre-dilution substitution fluid, or to provide a dialysate solution.

System 400 operates similarly to the blood filtration circuitspreviously described. In this circuit, a source of citrate ions iscombined with, and provided from, a source of substitution fluid 45.Pump 53 may pump fluid 45 through one or both of two flow paths 27 and29. Flow 27 provides a pre-dilution supplement with citrateanticoagulant to blood flow 20 entering hemofilter 39. Flow 29 providesa dialysate with citrate anticoagulant to dialysate flow path 32. Inthis fashion, a citrate anticoagulant may be applied along eithersurface of the hemofilter membrane, either as a pre-dilutionsubstitution fluid, or as a dialysate. When provided as a pre-dilutionsubstitution fluid, a sensor such as pressure sensor 73 may be used todetect flow 27, or flow rate, or pressure in the pre-dilution line. Notealso that citrate may be added through pump 53, thus system 400 may notrequire the separate citrate pump 19 or source of citrate solution 17,of system 200. In another embodiment, citrate may be added through apost-dilution substitution fluid.

FIG. 5 shows an exemplary schematic diagram of a system 500 according toanother embodiment of the invention for controlling components shown inFIGS. 2-4. As in the embodiment of system 100, a controller 11communicates to components within the blood filtration circuit viasignal line 12. Through this communication link, instrumentation such aselectrolyte sensor 15, blood leak detector 46, temperature sensor 55,air bubble detector 67, and pressure sensors 13, 35, 41, 47, and 73 maytransmit signals representing sensed or detected system parameters forinput to controller 11. In response to receiving input signals,controller 11 may automatically output control signals through signalline 12 for actuating components such as citrate pump 19, blood pump 31,heparin pump 33, pre-dilution pump 37, filtration pump 49, post-dilutionpump 53, electrolyte pump 65, and the automatic clamp 69. For example,one or more of the pressure sensors may provide feedback representing aflow rate to controller 11 for input to a PID or state-space controlalgorithm. The form of control signals automatically output fromcontroller 11 may be determined according to control algorithms storedin memory 23 and executed by CPU 21. Alternatively, CPU 21 may displaycalculated results on a display 25 for manual adjustment of systemparameters via user interface 27. In another embodiment, data may bestored in memory 23 (e.g. as a lookup table) for use in calculatingsystem control signals.

FIG. 6 is a flow chart showing a method 600 according to an embodimentof the invention for controlling citrate pump flow rate during CRRTtreatment using regional citrate anticoagulation. The steps of method600 may be carried out either manually or automatically.

Method 600 begins with step 81. In this first step, a blood flow ratedenoted A may be detected in a patient undergoing CRRT. A blood flowdetector 13 may be used to perform this step. The blood flow detectormay be operated manually by a health care worker, or automatically as anintegral component of a system per the invention. The next step 82 isanother detecting step, in which calcium concentration B is detected ina blood sample from the patient. Again, this step may be performedautomatically by the system or manually by a worker using an electrolytesensor suitable for the purpose.

In the next step 83, a citric acid concentration C may be selected forthe therapy. The citric acid concentration may be selected for apre-dilution substitution fluid, for a post-dilution substitution fluid,or for a dialysate solution. Next, in step 84, a concentration D ofmagnesium in a blood sample of the patient may be detected, manually orautomatically, using an appropriate electrolyte sensor. The next step inthe sequence is step 85, which is an optional step, depending on whetherequation (1) or equation (2) is used in the final calculation of step611. If equation (1) is used, step 85 may not be performed. If equation(2) is used, step 85 may be performed by selecting a trisodium citrateconcentration G as an anticoagulant for supplementing blood flow in anextracorporeal filtration circuit. The trisodium citrate concentration Gmay be selected for a pre-dilution substitution fluid, for apost-dilution substitution fluid, or for a dialysate solution.

The final step of method 600 is step 86. In step 86 a calculation isperformed for controlling citrate flow rate E, or equivalently, forcontrolling the flow rate E of a citrate pump, substitution pump, ordialysate pump, depending on which pump has been selected to provide asource of citrate ions. If optional step 85 has not been performed, step86 controls citrate flow rate according to equation (1). If optionalstep 85 has been performed, step 86 controls citrate flow rate accordingto equation (2), as shown in FIG. 6. In either case, step 86 may beperformed automatically using a controller such as controller 11. Inthis case, controller 11 would perform step 86 in response to receivinginput signals for the parameters A, B, C, D, and G corresponding to thepreceding steps of the method.

Alternatively, one or more steps of method 600 may also represent manualinput of a system parameter into a formula for calculating citrate flowrate. For example, each step may be performed manually, usingappropriate instrumentation. Then at step 86, a user inputs the resultsof all preceding steps into a controller. A user interface may be usedfor this purpose. In response to the inputs, the controller mayautomatically adjust citrate pump flow rate using an appropriatecalculation. It should be appreciated that steps 81 to 85 of method 600need not be performed in the sequence illustrated. Any sequence, orsimultaneous performance of these steps, may produce a desired result inthe final step 86.

FIG. 7 is a flow chart showing a method 700 according to an embodimentof the invention for controlling electrolyte pump flow rate during CRRTtreatment using regional citrate anticoagulation. Method 700 may beperformed in conjunction with method 600. In method 700, an electrolytepump (e.g. pump 65) may provide calcium ions and magnesium ions toreplenish these electrolytes that are lost in the filtration process.

Method 700 begins at step 87, in which a calcium ion concentration [Ca]may be selected for an electrolyte solution. Similarly, in step 88, amagnesium ion concentration [Mg] may be selected for an electrolytesolution. In one embodiment, [Ca] and [Mg] are selected for a commonchloride based solution.

In the next step 81, a blood flow rate, A, may be detected for a patientundergoing CRRT. In one embodiment, this step may be identical to step81 of method 600. Another detection step may be performed in step 89. Instep 89, a fluid loss rate, S, may be detected by measuring the rate ofplasma migration across the semi-permeable membrane of an artificialkidney in service during CRRT. Fluid loss rate S may be detected byvolumetric measurement of the plasma over time, or by an appropriateflow or pressure sensor (such as sensor 47) placed in an outflow line ofthe hemofilter (i.e. flow path 32). In one example where dialysate flowis present, subtracting a known dialysate flow rate from the hemofilteroutflow rate will yield a value for S. One or more of steps 81, 87, 88,and 89 may be data collection or data input steps, and may be performedsimultaneously, or in any desired sequence.

The final step in method 700 is step 90, which may be a calculation andcontrol step. In this step, a calculation may be performed forcontrolling the electrolyte pump flow rate V. In one embodiment, step 90calculates V as a function of [Ca], [Mg], A, and S. The result of thiscalculation may be automatically or manually transmitted as an inputcontrol signal to the electrolyte pump to control the introduction ofelectrolytes into the blood flow after filtration.

FIG. 8 is a flow chart showing a method 800 according to anotherembodiment of the invention for calculating ultrafiltration rate duringCRRT treatment using regional citrate anticoagulation. Method 800 may beused in conjunction with methods 600 and 700 for controlling the overallCRRT process.

Method 800 may contain three steps for acquiring input data for itsfinal calculation. The first of these steps is step 86, for calculatinga citrate pump flow rate E. This step may be performed identically as instep 86 of method 600. The second step is step 89, which may be adetection step for detecting fluid loss rate S. This step may beperformed identically as in step 89 of method 700. The third step isstep 90, for calculating an electrolyte pump flow rate V. Step 90 may beperformed identically as in step 90 of method 700. Once the input datahas been acquired from these three steps, simultaneously or in anysequential order, a final calculation step 91 may be executed. In step91, an ultrafiltration rate I may be calculated as a function of E, S,and V.

FIG. 9 is a flow chart showing a method 900 according to an embodimentof the invention for controlling post dilution flow rate during CRRTtreatment using regional citrate anticoagulation. Method 900 may also beused in conjunction with methods previously disclosed for comprehensivecontrol of a CRRT system according to the invention.

The first three steps illustrated in the flow chart of FIG. 9 may beperformed identically or in a similar manner to previously describedsteps. Step 81 may be performed as in method 600 to detect a blood flowrate A. Step 85 may be performed as in method 600 to select a trisodiumcitrate concentration G. Step 91 may be performed as in method 800 tocalculate an ultrafiltration rate I.

In the next step 92, a sodium concentration, P, may be selected for apre-dilution substitution solution used for supplementing the blood flowin the extracorporeal circuit. For example, step 92 may includespecifying an appropriate sodium concentration for substitution fluidsource 43 in system 200. The next step, 93, may be a detection step fordetecting a pre-dilution fluid flow rate, Y. A flow sensor, a pressuresensor (e.g. sensor 73), or combination of pressure sensors may beplaced in the flow path of the pre-dilution fluid or elsewhere in thecircuit to detect this flow rate.

The final step of method 900 is step 94. The steps preceding step 94 maybe performed simultaneously or in any convenient sequence. In step 94, acalculation may be performed using the results of the preceding processsteps as inputs to arrive at an output value for controlling the flowrate, R, of the post-dilution substitution fluid. That is, R may becalculated as a function of A, G, I, P and Y. In one embodiment, thiscalculation may be performed automatically to control the output flowrate delivered by a post dilution pump 53.

FIG. 10 is a flow chart of an embodiment of a method according to theinvention that illustrates the interdependency of the various input andoutput parameters described in all of the foregoing methods. In thischart, method 1000 combines methods 600, 700, 800, and 900 into a singlemethod for deriving output parameters, from components of a bloodfiltration circuit, for automating and optimizing CRRT treatment usingregional citrate anticoagulation according to the invention.

There are three types of process blocks illustrated in the chart of FIG.10. A rectangular block denotes a selection step, wherein a processinput parameter such as a chemical concentration may be selected. Adiamond shaped block denotes a detection step, wherein a process inputparameter such as a flow rate may be detected. A circular block denotesa calculation step, which may produce a process input parameter or aprocess output parameter. Arrows originate from process input steps andterminate at process output steps. Each of the calculation steps shownin the chart provides a flow rate, and all flow rates are interdependentin order to optimize system operation.

Thus, according to the invention, citrate pump flow rate E may be afunction of blood flow rate A, patient calcium concentration B, citricacid concentration C, patient magnesium ion concentration D, andtrisodium citrate concentration G.

Electrolyte pump flow rate V may be a function of blood flow rate A,calcium solution concentration [Ca], magnesium solution concentration[Mg], and fluid loss rate S.

Ultrafiltration rate I may be a function of citrate pump flow rate E,fluid loss rate S, and electrolyte pump flow rate V.

And, post-dilution pump flow rate R may be a function of blood flow rateA, trisodium citrate concentration G, ultrafiltration rate I,pre-dilution substitution solution sodium concentration P, andpre-dilution flow rate Y.

The following sections provide additional disclosure of algorithms thatmay be used to optimize CRRT therapies according to various embodimentsof the present invention. One or more of the algorithms may use codesthat are listed in Table 1 below. The table includes a description ofthe parameter and definition of the parameter represented by each code.The table also indicates in the right-most column whether the parameteris selected, detected, or calculated. Dimensional units such as (ml/min)are provided for illustrative purposes only.

TABLE 1 CODE PARAMETER DEFINITION TYPE A blood flow rate (ml/min) range:30 to 450 ml/min detected A′ plasma flow rate (ml/min) depends on A andhematocrit: calculated A′ = A × (1 − Hct) B Pca (mmol/l) patient plasmaconcentration detected of calcium (0.8 to 1.6 mmol/l) C Ctcitrate (mmol)concentration of citrate selected D Pmg patient plasma concentration ofdetected Magnesium (0.55 to 1.15 mmol/l) E citrate flow rate (ml/h)citrate flow rate needed to chelate all calculated Ca and Mg ions frompatient plasma F Pna (mmol/l) patient plasma concentration of Nadetected (125 to 155 mmol/l) G Nacitrate (mmol/l) sodium concentrationin citrate solution selected H Na in (mmol/h) no. of mmol of Na enteringhemofilter calculated per hour I UF rate (ml/h) filtration amount notreturned to patient calculated J blood flow rate out (ml/min) blood flowrate just after hemofilter calculated K Na filtered (mmol/h) no. of Namolecules filtrated per hour calculated L Na out (mmol/h) no. of plasmaNa molecules exiting the calculated Hemofilter per hour M Na+ sievingcoefficient sieving coefficient of Na thru hemofilter selected M′trisodium citrate sieving coefficient of trisodium citrate selectedsieving coefficient thru the hemofilter N filtration flow rate (ml/h)total filtration volume thru hemofilter calculated O Na in (mmol/l)plasma concentration of Na just before calculated the hemofilter P Napre-dilution (mmol/l) Na concentration of pre-dilution selectedsubstitution solution P′ Na post-dilution Na concentration ofpost-dilution selected substitution solution R substitution flow ratepost-dilution substitution flow rate calculated S fluid loss rate (ml/h)desired fluid loss rate for the patient, detected per hour (0 to 2000ml/h) T Cacitrate sieving sieving coefficient of calcium citrateselected coefficient thru the hemofilter T′ calcium sieving coefficientsieving coefficient of calcium thru selected the hemofilter U Casolution concentration concentration of calcium in chloride selected(mmol/l) Ca/Mg solution V Ca/Mg flow rate (ml/h) flow rate of chlorideCa/Mg solution calculated W Ca citrate in (mmol/h) no. of plasmacalcium-citrate molecules calculated entering the hemofilter Xfiltration fraction filtration fraction thru the hemofilter calculated Ypre-dilution flow rate (ml/h) flow rate of pre-dilution substitutionfluid detected Z total fluid loss (ml) total fluid loss expected for thepatient detected AA Na inside Ca/Mg concentration of sodium inside Ca/Mgselected complementary solution AB protidemia (g/L) total weight ofproteins in 1 L of plasma calculated Before hemofilter AC MgCitratesieving sieving coefficient of MagnesiumCitrate selected Coefficientmolecules thru the hemofilter AD bicarbonate sieving sieving coefficientof bicarbonate ions selected coefficient (HCO3—) AE Pbicar (mmol/L)patient plasma concentration of detected bicarbonate (mmol/l) AF citricacid sieving sieving coefficient of citric acid coming selectedcoefficient from citrate solution AG Ca++ post concentration Ca++concentration of post-dilution selected substitution solution

Citrate Flow Rate

Automatic regulation of citrate flow rate during CRRT in any of thesystems herein described may be implemented according to the rulesprovided in the following Table 2:

TABLE 2 CONDITION ADJUSTMENT AG > 0.5 mmol/L increase E by 2.5 mmol/h0.4 < AG < 0.5 mmol/L increase E by 1.5 mmol/h 0.2 < AG < 0.4 mmol/L nochange AG < 0.2 mmol/L decrease E by 1.5 mmol/h 7.45 < plasma pH < 7.55increase E by 1.5 mmol/h plasma pH > 7.55 increase E by 2.5 mmol/hincrease in plasma total calcium adjust E per equation (1) or (2)decrease in plasma total calcium adjust E per equation (1) or (2)increase in plasma total magnesium adjust E per equation (1) or (2)decrease in plasma total magnesium adjust E per equation (1) or (2)increase in A adjust E per equation (1) or (2) decrease in A adjust Eper equation (1) or (2)

Each of the rules described in the above table may be implementedmanually under by a health care worker by manipulating instrumentsdirectly, or through a user interface to a controller described, forexample, in system 100 or system 500. The same rules may be implementedautomatically by a controller executing an adjustment algorithm storedas a series of instructions or software in memory executable by thecontroller CPU.

Filtration Flow Rate, N

The total filtration flow rate N may be calculated by accounting for thepresence of sodium in the circuit. The amount of sodium after additionof the post-dilution substitution solution equals the amount of sodiumentering the hemofilter, plus the amount of sodium introduced by thepost-dilution substitution solution, minus the amount of sodium lostthrough the hemofilter. This may be expressed algebraically as:N={[(F×60×A′−S)−(V×AA)]−H×1000+P′×(Y+E+V+S)}/{[P−(M×H/(60×A′+E+Y))]×1000×1000/(1000−AB)}  (3)or as:N={[(F×60×A′−S)−(V×AA)]−H×1000+P′×(Y+E+V+S)}/{[P′−1000×1000/(1000−AB)]×[M×(H−3×H′)+M′×3×H′]/(60×A′+E+Y)}  (4)where H′ represents the number of excess trisodiumcitrate moleculescirculating per hour through the hemofilter. H′ may be given by:H′=[C×E)/1000−(B+D)×60×A′/1000]×(G/3)/C  (5)

Post-dilution Flow Rate, R

The filtration flow rate N is the sum of the post-dilution flow rate R,the pre-dilution flow rate Y, the citrate solution flow rate E, theCa/Mg solution flow rate V, and the fluid loss rate S. Therefore, thepost-dilution substitution fluid flow rate, R, may be calculatedaccording to:R=N−(E+S+V+Y)  (6)

Calcium/Magnesium Pump Flow Rate, V

A method according to the invention for calculating an optimal Ca/Mgpump flow rate V may be based on an assumption that the total calciumconcentration of blood entering the extracorporeal circuit is equivalentto the total calcium concentration returning to the patient at the exitof the circuit in order to maintain a stable calcemia. Thus, the calciumreturning to the patient may be equivalent to the calcium content beforethe hemofilter, plus the calcium contribution from the post-dilutionsubstitution solution, plus the calcium contribution from the Ca/Mgelectrolyte solution, minus the calcium lost through the hemofilter.

Two situations may occur that affect the algorithm chosen forcalculating V. The first situation occurs when trisodium citratemolecules introduced into the blood flow are not sufficient to chelateall calcium and magnesium from the blood circulating upstream of thehemofilter. In this case, the Ca/Mg pump flow rate V may be calculatedas:V=[B×(60×A′−S)/1000−W+(α×β)/γ]×γ/(AA−P′)×β+(U/1000)×γwhereα=[F×(60×A′−S)−H×1000+P′×(Y+E+S)];β=1000×[T×((E×C/1000)×(B/(B+D))]+T′×(½)[W−(E×C/1000)×(B/(B+D))];andγ=P′×(60×A′+E+Y)×(1000−AB)−M×H×1000×1000  (7)

In this first situation, it may be of interest, to calculate the numberof calcium molecules filtrated through the hemofilter. The number ofcalcium molecules filtrated per hour, denoted as “Cafiltrated_(—)1”, maybe calculated as:Cafiltrated_(—)1=[α−(V×AA)]×β/γ  (8)

In the second situation, the trisodium citrate molecules are sufficientto chelate all calcium and magnesium from the blood circulating upstreamof the hemofilter. In this case, the Ca/Mg pump flow rate V may becalculated as:V=[B×(60×A′−S)/1000−W+(δ/ε)×ε/[1000×T×W×V×(AA−P′)+U/1000×ε]whereδ=1000×T×W×(F×(60×A′−S)−H×1000+P′×(Y+E+S)); andε=P′×(60×A′+E+Y)×(1000−AB)−1000×1000×(M×(H−3×H′)+M′×3×H′)  (9)

In this second situation, the number of calcium molecules filtrated perhour, denoted as “Cafiltrated_(—)2”, may be calculated as:Cafiltrated_(—)2=100×T×W×(F×(60×A′−S)−(V×AA)−H×1000+P′×(Y+E+V+S))/(60×A′+E+Y)×(1000−AB)×(P′−1000×(1000/(1000−AB))×(M×(H−3×H′)+M′×3×H′)/(60×A′+E+Y))  (10)

Equations (8) and (10) may also be used to calculate the number ofmagnesium molecules filtrated through the hemofilter, by simplyreplacing the parameter B with D.

Bicarbonates Filtrated

Bicarbonate concentration in blood plasma during CRRT using regionalcitrate anticoagulation may also be of concern. Citrate added to theextracorporeal circuit through citrate anticoagulant solution (citricacid and trisodium citrate) will be converted later by the liver andmuscles of the patient into bicarbonate according to thetri-carboxycilique cycle from the Krebs cycle. The present invention mayalso account for citrate converted into bicarbonate in this manner, bymonitoring eventual bicarbonate concentration in the blood plasmareturned to the patient. The invention may account for bicarbonatemolecules under two different cases.

In the first case, the amount of bicarbonate molecules, BICout_(—)1, maybe calculated where the number of citrate molecules introduced by thecitrate solution is equal to or less than the sum of total calcium andtotal magnesium present in the blood plasma. In this case, the followingequation may be used:BICout_(—)1=N×[AD×EA×60×A′+T×E×C×B+AC×E×C×D]/[1000×(B+D)×(1000−AB)×(60×A′+E+Y)]  (11)

In the second case, the amount of bicarbonate molecules, BICout_(—)2,may be calculated where the number of citrate molecules introduced bythe citrate solution is greater than the sum of total calcium and totalmagnesium present in the blood plasma. In this case, the followingequation may be used:BICout_(—)2=N×[AD×AE×60×A′+M′×E×G/3−M′×(B+D)×60×A′×(G/3)/C+AF×E×(C−G/3)−AF×(B+D)×60×A′×(C−G/3)/C+T×B×60×A′+AC×D×60×A′]/[1000×(1000−AB)×(60×A′+E+Y)]  (12)

Proofs for equations (1) through (12) are provided in U.S. ProvisionalApplication 60/719,718.

Treatment Control

An embodiment of a system or method according to the invention mayevaluate the composition of plasma circuit with regard to eachelectrolyte in the CRRT circuit in a step-by-step manner. The followingtables provide formulas that may be used progressively to accuratelycalculate the number of molecules or concentration of any electrolyte ofinterest under various conditions and at various points in the circuit.The formulas shown in the tables may be stored as algorithms in a memory23 as software executable by a CPU 21. The results of the calculationsmay be used in many ways. For example, the results may stored in memory23, used as input in other algorithms, or displayed to a user viadisplay unit 25.

Table 3 provides formulas for calculating the number of molecules ofeach electrolyte circulating per hour in the extracorporeal circuit.

Table 4 provides formulas for calculating the number of molecules ofeach electrolyte circulating per hour after citrate addition.

Table 5 provides formulas for calculating the number of molecules ofeach electrolyte circulating per hour after the addition of pre-dilutionsubstitution solution.

Table 6 provides formulas for calculating the number of molecules ofeach electrolyte filtrated through the hemofilter per hour.

Table 7 provides formulas that may be used to calculate the number ofmolecules per hour for any particular electrolyte passing downstream ofthe hemofilter.

Table 8 provides formulas that may be used to calculate the number ofmolecules of each electrolyte circulating per hour after the addition ofpost-dilution substitution solution.

Table 9 provides formulas for calculating the number of molecules ofeach electrolyte returning to the patient.

Table 10 provides formulas for calculating the plasma concentration ofeach electrolyte returning to the patient.

TABLE 3 PATIENT PLASMA CONCENTRATION NO. OF MOLECULES ELECTROLYTE(mmol/L) PER HOUR (mmol/h) total calcium TCA 60 × A′ × TCA/1000 totalmagnesium TMG 60 × A′ × TMG/1000 sodium NA 60 × A′ × NA/1000 potassium K60 × A′ × K/1000 glucose GLU 60 × A′ × GLU/1000 bicarbonates BIC 60 × A′× BIC/1000 phosphate PH 60 × A′ × PH/1000 chlorides CL 60 × A′ × CL/1000

In Table 4, the concentration of a particular electrolyte in citratesolution is denoted by an abbreviation for the electrolyte preceding theterm “citrate”. For example, “Na_citrate” denotes the concentration ofsodium in citrate solution.

TABLE 4 NO. OF MOLECULES ELECTROLYTE PER HOUR AFTER CITRATE (mmol/h)total calcium 60 × A′ × TCA/1000 total magnesium 60 × A′ × TMG/1000sodium 60 × A′ × NA/1000 + E × Na_citrate/1000 potassium 60 × A′ ×K/1000 + E × K_citrate/1000 glucose 60 × A′ × GLU/1000 + E ×Glu_citrate/1000 bicarbonates 60 × A′ × BIC/1000 + E × Bic_citrate/1000phosphate 60 × A′ × PH/1000 + E × Pho_citrate/1000 chlorides 60 × A′ ×CL/1000 + E × Cl_citrate/1000

In Table 5, the concentration of a particular electrolyte inpre-dilution substitution solution is denoted by an abbreviation for theelectrolyte preceding the term “pre”. For example, “Ca_pre” denotes theconcentration of calcium in pre-dilution substitution solution.

TABLE 5 NO. OF MOLECULES PER HOUR ELECTROLYTE AFTER PRE-DILUTION SUB.SOLN. (mmol/h) total calcium (CAin) 60 × A′ × TCA/1000 + Y × Ca_pre/1000total magnesium 60 × A′ × TMG/1000 + Y × Mg_pre/1000 (MGin) sodium(NAin) 60 × A′ × NA/1000 + E × Na_citrate/1000 + Y × P/1000 potassium(Kin) 60 × A′ × K/1000 + E × K_citrate/1000 + Y × K_pre/1000 glucose(GLUin) 60 × A′ × GLU/1000 + E × Glu_citrate/1000 + Y × Glu_pre/1000bicarbonates 60 × A′ × BIC/1000 + E × Bic_citrate/1000 + Y × (BICin)Bic_pre/1000 phosphate (PHin) 60 × A′ × PH/1000 + E × Pho_citrate/1000 +Y × Pho_pre/1000 chlorides (CLin) 60 × A′ × CL/1000 + E ×Cl_citrate/1000 + Y × Cl_pre/1000

In Table 6, the sieving coefficient for a particular electrolyte isdenoted by the term “Sie” preceding an abbreviation for the electrolyte.For example, “Sie_K” denotes the sieving coefficient for potassium.

TABLE 6 NO. OF MOLECULES PER HOUR FILTRATED THROUGH HEMOFILTERELECTROLYTE (mmol/h) total calcium (CAout) per equation (8) or equation(10) total magnesium (MGout) per eq. (8) or eq. (10) by replacing B withD sodium (NAout) per eq. (3) or eq. (4) potassium (Kout) (1000/(1000 −AB)) × Sie_K × N/(60 × A′ + E + Y) glucose (GLUout) (1000/(1000 − AB)) ×Sie_Glu × N/(60 × A′ + E + Y) bicarbonates (BICout) per eq. (11) or eq.(12) phosphate (PHout) (1000/(1000 − AB)) × Sie_Pho × N/(60 × A′ + E +Y) chlorides (CLout) (1000/(1000 − AB)) × Sie_Cl × N/(60 × A′ + E + Y)

TABLE 7 NO. OF MOLECULES PER ELECTROLYTE HOUR AFTER HEMOFILTER (mmol/h)total calcium CAin − CAout total magnesium MGin − MGout sodium NAin −NAout potassium Kin − Kout glucose GLUin − GLUout bicarbonates BICin −BICout phosphate PHin − PHout chlorides CLin − CLout

In Table 8, the post-dilution substitution solution concentration for aparticular electrolyte is denoted by an abbreviation for the electrolytepreceding the term “post”. For example, “K_post” denotes theconcentration of potassium in the post-dilution substitution solution.

TABLE 8 NO. OF MOLECULES PER HOUR AFTER ELECTROLYTE POST DILUTION SUB.SOLN. (mmol/h) total calcium CAin − Caout + Ca_post × R/1000 totalmagnesium MGin − Mgout + Mg_post × R/1000 sodium NAin − Naout + Na_post× R/1000 potassium Kin − Kout + K_post × R/1000 glucose GLUin − GLUout +Glu_post × R/1000 bicarbonates BICin − BICout + Bic_post × R/1000phosphate PHin − PHout + Pho_post × R/1000 chlorides CLin − CLout +Cl_post × R/1000

In Table 9, the Ca/Mg complementation solution concentration for aparticular electrolyte is denoted by an abbreviation for the electrolytepreceding the term “Cp”. For example, “Bic_Cp” denotes the CaMgcomplementation solution concentration of bicarbonate.

TABLE 9 NO. OF MOLECULES PER ELECTROLYTE HOUR AT PATIENT RETURN (mmol/h)total calcium (CAretum) CAin − CAout + Ca_post × R/1000 + Ca_Cp × V/1000total magnesium (MGreturn) MGin − MGout + Mg_post × R/1000 + Mg_Cp ×V/1000 sodium (NAreturn) NAin − NAout + Na_post × R/1000 + Na_Cp ×V/1000 potassium (Kreturn) Kin − Kout + K_post × R/1000 + K_Cp × V/1000glucose (GLUreturn) GLUin − GLUout + Glu_post × R/1000 + Glu_Cp × V/1000bicarbonates (BICreturn) BICin − BICout + Bic_post × R/1000 + Bic_Cp ×V/1000 phosphate (PHreturn) PHin − PHout + Pho_post × R/1000 + Pho_Cp ×V/1000 chlorides (CLreturn) CLin − CLout + Cl_post × R/1000 + Cl_Cp ×V/1000

TABLE 10 PLASMA CONCENTRATION ELECTROLYTE AT PATIENT RETURN (ml/min)total calcium 1000 × CAreturn/(60 × A′ − S) total magnesium 1000 ×MGreturn/(60 × A′ − S) sodium 1000 × NAreturn/(60 × A′ − S) potassium1000 × Kreturn/(60 × A′ − S) glucose 1000 × GLUreturn/(60 × A′ − S)bicarbonates 1000 × BICreturn/(60 × A′ − S) phosphate 1000 ×PHreturn/(60 × A′ − S) chlorides 1000 × CLreturn/(60 × A′ − S)

CONCLUSION

Prior methodologies cited in the background section provide insufficientguidance for controlling citrate flow into the bloodstream during CRRT.At a blood flow rate of 200 ml/min, the recommendation for citrate flowamong these sources varies from 28 to 52.5 mmol/h, with a mean value of36.6 mmol/h. However, applying a method according to the presentinvention to each of the systems in the cited literature, a mean valueof 39.6 mmol/h citrate flow was achieved for a 200 ml/min blood flowrate. This mean value was achieved with minimal variance of 0.005 (seeU.S. Provisional Application 60/719,718). Thus, the present inventionprovides consistent results regardless of the type of CRRT, andregardless of the blood flow rate chosen.

A further advantage provided by the invention is that it works equallywell regardless of where citrate enters the circuit. Citrate may enteras a pre-dilution solution, as part of a pre-dilution substitutionsolution, or as part of a dialysate. Another advantage is that theinvention may control the instantaneous blood flow rate, and alsoautomatically adjust the citrate flow rate whenever blood flow ratechanges. Another advantage is that the invention ensures that the plasmaconcentration of vital electrolytes returns to the patient at safelevels, e.g. total plasma calcium and magnesium concentrations of bloodreturning to the patient are equivalent to the concentrations enteringthe extracorporeal circuit. Another advantage is that the inventionadjusts its control algorithms according to whether excess trisodiumcitrate is present in the circuit.

Another advantage is that the system may provide a health careprofessional with instantaneous data regarding flow rates, bloodchemistry, and electrolyte levels on a convenient real-time display. Atechnician may therefore evaluate conditions and initiate manualadjustment of treatment parameters, as desired. By using a controlsystem according to the invention, a technician may compare theconsequences of optimized treatment parameters on plasma concentrationof blood returning to the patient, or compare the consequences ofautomated treatment parameters controlled by software. Results may alsobe recorded in system memory, to collect historical data for provingoptimization. The technician may also optimize treatment for specificcases in this manner. For example, parameters may need to be manuallyadjusted or manually input to the automatic control system to optimizetreatment based on patient weight, gender, or other physicalcharacteristics or infirmities.

The invention has been disclosed in an illustrative style. Accordingly,the terminology employed throughout should be read in an exemplaryrather than a limiting manner. Although minor modifications of thepresent invention will occur to those well versed in the art, it shallbe understood that what is intended to be circumscribed within the scopeof the patent warranted hereon are all such embodiments that reasonablyfall within the scope of the advancement to the art hereby contributed,and that that scope shall not be restricted, except in light of theappended claims and their equivalents.

The invention claimed is:
 1. A blood filtration system, comprising: afiltration circuit including a filter having a dialysis solutionchamber; a blood pump configured to pump blood through the filtrationcircuit; a source of citrate anticoagulant solution having apredetermined citrate anticoagulant solution concentration; a citrateanticoagulant pump positioned and arranged to pump citrate anticoagulantsolution from the citrate anticoagulant solution source into thefiltration circuit; a dialysis solution pump positioned and arranged topump a citrate dialysis solution into the dialysis solution chamber ofthe filter; a controller configured to control the citrate anticoagulantpump to control the flow rate of the citrate anticoagulant solution fromthe citrate anticoagulant pump according to an algorithm that takes intoaccount at least: (i) a blood flow rate, (ii) a concentration of thecitrate anticoagulant solution, and (iii) an electrolyte concentration;and an electrolyte sensor that detects an configured to detect theelectrolyte concentration, wherein the controller includes a processorthat is configured to receive an input from the electrolyte sensor thatrepresents the detected electrolyte concentration.
 2. The system ofclaim 1, wherein the controller further includes: software, executableby the processor, for executing the algorithm.
 3. The system of claim 1,which includes a blood flow detector for detecting a flow of blood fromthe patient, and wherein the controller controls a flow from the citrateanticoagulant pump as a function of the detected blood flow rate, andthe concentration of the citrate anticoagulant solution.
 4. The systemof claim 1, wherein the electrolyte sensor detects concentration in theblood flow of an ion selected from the group consisting of bicarbonate,calcium, chloride, copper, glucose, iron, magnesium, manganese,phosphate, potassium, sodium, and zinc.
 5. The system of claim 4,wherein the algorithm includes a citrate anticoagulant pump flow rate,E, determined according to E(A, B, C, D)=Ax(B+D)/C, wherein A is adetected blood flow rate, B is a calcium ion concentration detected bythe electrolyte sensor, C is the concentration of the citrate solution,and D is a magnesium ion concentration detected by the electrolytesensor.
 6. The system of claim 1, further comprising: a blood flowdetector for detecting a flow of blood from the patient; a sensor fordetecting fluid loss rate in the blood filtration circuit; anelectrolyte solution having a selected calcium ion concentration and aselected magnesium ion concentration; and an electrolyte pump positionedand arranged to pump the electrolyte solution to supplementpost-filtration blood flow, wherein the controller controls the flowfrom the electrolyte pump as a function of the detected blood flow, thedetected fluid loss rate, the selected calcium ion concentration, andthe selected magnesium ion concentration.
 7. The system of claim 1,wherein the controller further includes: software, executable by theprocessor, (i) for accepting a detected fluid loss rate in the bloodfiltration circuit, (ii) for determining a desired citrate anticoagulantpump flow rate and a desired electrolyte pump flow rate, and (iii) forcalculating an ultrafiltration rate as a function of the detected fluidloss rate, the desired citrate anticoagulant pump flow rate, and thedesired electrolyte pump flow rate.
 8. The system of claim 7, whereinthe citrate anticoagulant solution has a selected trisodium citrateconcentration, the system further including; a substitution solutionhaving a selected sodium concentration; a substitution solution pumppositioned and arranged to pump the substitution solution to supplementthe blood flow; a sensor for detecting substitution solution flow rate;and the controller is further configured to determine a post-dilutionflow rate as a function of the detected blood flow rate, the selectedtrisodium citrate concentration, the calculated ultrafiltration rate,the selected sodium concentration of the substitution solution, and thedetected substitution solution flow rate.
 9. The system of claim 1,which is configured to use the citrate anticoagulant solution tosupplement the blood flow as a pre-dilution solution in the bloodfiltration circuit.
 10. The system of claim 1, wherein the citrateanticoagulant solution enters the blood filtration circuit as part of adialysate.
 11. The system of claim 1, which includes a source of citratedialysis solution.
 12. The system of claim 11, wherein the citratedialysis solution is pumped from the source of citrate dialysis solutionwith the dialysis solution pump.
 13. A blood filtration systemcomprising: a filter including a dialysis solution chamber; a blood pumpconfigured to pump blood to the filter; a supply of citrateanticoagulant solution; a citrate anticoagulant pump connected to thesupply of citrate anticoagulant solution, the citrate anticoagulant pumppositioned and arranged to pump the citrate anticoagulant solution intothe filter; a dialysis solution pump positioned and arranged to pump adialysis solution including citrate into the dialysis solution chamberof the filter to filter the blood; and a controller configured tocontrol the citrate anticoagulant pump to control the flow rate ofcitrate anticoagulant solution from the citrate anticoagulant pumpaccording to an algorithm that takes into account at least one of: (i) ablood flow rate, (ii) a concentration of the citrate anticoagulantsolution, and (iii) an electrolyte concentration; and an electrolytesensor configured to detect the electrolyte concentration, wherein thecontroller includes a processor that is configured to receive an inputfrom the electrolyte sensor that represents a detected electrolyteconcentration.
 14. The system of claim 13, wherein the controllerfurther includes: software, executable by the processor, for determininga desired flow of citrate anticoagulant solution from the supply ofcitrate anticoagulant solution.
 15. The system of claim 13, whichincludes a blood flow detector for detecting a flow of blood from thepatient, and wherein the controller controls the flow from the citrateanticoagulant pump as a function of the detected blood flow rate and theconcentration of the citrate anticoagulant solution.
 16. The system ofclaim 13, wherein the electrolyte sensor detects concentration in theblood flow of an ion selected from the group consisting of bicarbonate,calcium, chloride, copper, glucose, iron, magnesium, manganese,phosphate, potassium, sodium, and zinc.
 17. The system of claim 16,wherein the algorithm includes a citrate anticoagulant pump flow rate,E, determined according to E(A, B, C, D)=Ax(B+D)/C, wherein A is adetected blood flow rate, B is a calcium ion concentration detected bythe electrolyte sensor, C is the concentration of the citrate solution,and D is a magnesium ion concentration detected by the electrolytesensor.
 18. The system of claim 13, which includes: a blood flowdetector for detecting a flow of blood from the patient; a sensor fordetecting fluid loss rate in a blood filtration circuit including thefilter; an electrolyte solution having a selected calcium ionconcentration and a selected magnesium ion concentration; and anelectrolyte pump positioned and arranged to pump the electrolytesolution to supplement post-filtration blood flow, wherein thecontroller controls the flow from the electrolyte pump as a function ofthe detected blood flow, the detected fluid loss rate, the selectedcalcium ion concentration, and the selected magnesium ion concentration.19. The system of claim 18, wherein the controller further includes:software, executable by the processor, for (i) accepting a detectedfluid loss rate in a blood filtration circuit including the bloodfilter, (ii) determining a desired citrate anticoagulant pump flow rateand a desired electrolyte pump flow rate, and (iii) for calculating anultrafiltration rate as a function of the detected fluid loss rate, thedesired citrate anticoagulant pump flow rate, and the desiredelectrolyte pump flow rate.
 20. The system of claim 19, furthercomprising: the citrate solution having a selected trisodium citrateconcentration; a substitution solution having a selected sodiumconcentration; a substitution solution pump causing flow of thesubstitution solution supplementing the blood flow; and a sensor fordetecting substitution solution flow rate, wherein the controllerfurther determines a post-dilution flow rate as a function of thedetected blood flow rate, the selected trisodium citrate concentration;the calculated ultrafiltration rate, the selected sodium concentrationof the substitution solution, and the detected substitution solutionflow rate.
 21. The system of claim 13, wherein the citrate anticoagulantsolution supplements the blood flow as a pre-dilution solution in theblood filtration circuit.
 22. The system of claim 13, wherein thecitrate solution enters the blood filtration circuit as part of adialysate.
 23. The system of claim 13, which includes a supply ofcitrate dialysis solution.
 24. The system of claim 23, wherein thedialysis solution including citrate is pumped from the supply of citratedialysis solution with the dialysis solution pump.